ASH 2018 | MRD and PFS correlation analysis of the phase III MURANO trial

On 3 December 2018, during the 60^th Annual Meeting of the American Society of Hematology (ASH), San Diego, CA, Arnon Kater from the University of Amsterdam, Amsterdam, NL, presented an updated analysis from the MURANO phase III trial (Abstract #695).

This abstract was presented during Oral Session 642 ‘CLL: Therapy, excluding Transplantation: Advances in CLL Using Novel Combination Therapy’ and provided the first prospective data on the impact of minimal residual disease (MRD) on long-term patient outcomes following the MURANO phase III trial. The MURANO trial demonstrated that fixed-duration venetoclax and rituximab (VenR) provide a significantly longer progression-free survival (PFS), compared to bendamustine and rituximab (BR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients. Here, peripheral blood (PB) MRD analysis related to long-term PFS outcomes from the MURANO study was performed.

Study design

• MURANO phase III trial: N = 389 R/R CLL patients were randomized to VenR (n = 194) or BR (n = 195)
• Dosing:
  • VenR: 5 weeks with gradual dose increase from 20 mg to 400 mg daily; then, for up to two years, 400 mg Ven daily and 375 mg/m² R
  • BR: 70 mg/m² B and 375 mg/m² R for six months
• PB MRD was analyzed by allele-specific oligonucleotide PCR and flow cytometry at the end of cycle 4, the end of combination therapy (EOCT; nine months) and every three months thereafter up to three years and every six months after that
• MRD and PFS correlations were performed at EOCT and end of treatment (EOT) time points
• Patients were categorized into:
  • uMRD (< 1 CLL cell per 10,000 leukocytes [< 10^–4])
  • Low MRD (≥10^–4 to <10^–2)
  • High MRD+ (≥10^–2)
• Results reported from the intention-to-treat (ITT) population

Results

• Median follow up: 36 months (May 2018). By then, 18% of patients progressed, died or withdrew from study in the VenR arm compared to 66% in the BR
• PB uMRD rates at EOCT:
  • VenR: 62% versus BR: 13%
• PB int-MRD rates:
  • VenR: 16% versus BR: 7%
• Consistently high uMRD rates were observed in all VenR subgroups, including patients with the high-risk cytogenetics and molecular factors (del[11q], del[17p], TP53 or immunoglobulin heavy-chain variable region gene [IGHV] mutation, bulky disease)
• Regardless of the arm (VenR or BR) uMRD status was associated with longer PFS (EOCT analysis)
• At EOCT, within the MRD positive patients, low MRD had better PFS than high MRD patients
• In the VenR and BR arm, uMRD patients who achieved complete or partial response had similar PFS
• Of the 130 patients in the VenR arm who completed two years Ven treatment without progressive disease (PD), 64% were uMRD, 18% low MRD and 10% high MRD (8% had missing data)
• At a median follow-up of 9.9 months following Ven completion, amongst the uMRD patients, 69% remained uMRD and 31% converted to confirmed MRD
  • Conversion to low MRD: 81% all of whom remained event-free at EOT
  • Conversion to high MRD: 19%
  • PD: n = 2
  • Of the patients converting to another MRD status, 40% carried del(17p) and/or TP53 mutation (versus 23% among those not MRD converting)

Conclusions

• PB uMRD at EOCT was predictive od prolonged PFS in both VenR and BR patients
• PFS was longer in patients with low MRD than those with high MRD
• MRD status was more valuable in outcome prediction than response data
• uMRD correlated with PFS of patients achieving either a complete or partial response
• At a median follow-up of 9.9 months after EOCT, PD and MRD conversion incidences were low